The inflammatory bowel diseases (IBD) involve complex abnormalities in the innate and adaptive immune response to the Intestinal microbiota. Data from experimental models has found that CD4 T cells are the effector cells mediating disease in most instances, that the enteric bacterial flora drives this pathologic response, and that the innate immune system (epithelium, dendritic cells, macrophages) is a critical link between these two elements. Thus, the major focus of this Program Project is on the interaction of the innate and adaptive immune responses with the microbiota and its products and on the genes that affect these interactions. The Program Project will be directed by Dr. Charles Elson and will consist of four Projects and two Cores. Project 1, headed by Dr. Elson, will use flagellins as probes of the normal T cell homeostatic response in the intestine. Studies will address the hypothesis that CD4 T cell effector subsets in the intestine maintain homeostasis by a number of different pathways that can compensate for one another, that these pathways have limits beyond which intestinal inflammation results, and that homeostasis can be restored by augmentation of regulatory T cells. Project 2, headed by Dr. Robin Lorenz, will use the mdr1a knockout model to address the hypothesis that the absence of the mdr1a encoded membrane pump leads to dysfunctional handling of xenobiotics, which results in abnormal development and function in cell types that express the aryl hydrocarbon receptor resulting in spontaneous. Project 3 will be headed by Dr. Casey Weaver who will continue his studies on Th17 cells in the intestine and their role in IBD and will use novel cytokine reporter and other mutant mouse lines to test the hypothesis that Th17 and Th1-like cells cooperate to sustain intestinal inflammation to intestinal microbiota antigens in IBD, that both cell types emerge from a common early Th17 developmental pathway, and that IL-23-dependent memory Th17 cells are required for sustained IBD pathogenesis. Project 4 is led by Dr. Stephan Targan at Cedars-Sinai Medical Center in Los Angeles, CA. This Project will continue to utilize a large panel of patient materials to define the Innate and adaptive Immune response in patients with Crohn's disease who have seroreactivity to CBir1 flagellins to test the hypothesis that immune response to CBIr1 flagellin defines a population of patients with genetic variations of the IL-23, IL-17, and IL-22 pathways, as well as variations in TL1A gene expression, resulting In a severe disease course in IBD. These Projects will be supported by an Administrative Core which will provide administrative support and coordination, and an Animal Model Core at U.A.B. which will centralize the production of mice with experimental colitis, provide for a central pathologic analysis, and generate stocks of genetically-modified stocks of mice for use in the Projects. The long-term goal is to increase our understanding of the fundamental mechanisms of IBD in order to develop better diagnostic and therapeutic strategies for patients.